Preparation for percutaneous absorption

ABSTRACT

The present invention provides a preparation for percutaneous absorption comprising as an effective component a prostaglandin I 2  derivative and a fatty acid or a derivative thereof, or a mixture of two or more of these, which has high percutaneous permeability of the PGI 2  derivative. Particularly, the present invention provides a preparation for percutaneous absorption comprising 5,6,7-trinor-4,8-inter-m-phenylene PGI 2  derivative and a C 6  -C 24  fatty acid, a salt thereof or an ester thereof, or a mixture of two or more of these, which has high percutaneous permeability of the PGI 2  derivative. This preparation for percutaneous absorption suggests a possibility to last pharmacological effects and to reduce side effects. Thus, the preparation is expected to be used for therapy of various diseases, aiming at topical and systemic actions.

This application is a 371 of PCT/JP95/02350, filed Nov. 16, 1995.

TECHNICAL FIELD

The present invention relates to a preparation for percutaneousabsorption, which comprises as an effective ingredient a prostaglandin(hereinafter referred to as "PG") I₂ derivative. More particularly, thepresent invention relates to a preparation to be percutaneouslyabsorbed, which comprises a fatty acid or a derivative thereof as anagent for enhancing percutaneous absorption, thereby percutaneouspermeability of the PGI₂ derivative is enhanced.

BACKGROUND ART

PGs are drugs drawing attention in various fields because they widelyoccur in various organs and body fluids and because they exhibit strongphysiological activities in a small amount. Among the PGs, PGI₂ has astrong activity to inhibit platelet aggregation and a strongvasodilation activity, so that use of PGI₂ as therapeutic agents forvarious diseases is expected.

However, since PGs including PGI₂ are very unstable chemically, theadministration route is limited to intravenous administration or thelike. Thus, studies are now being made for developing a stablederivative thereof and for looking for a novel administration route andadministration form.

Studies of preparations to be percutaneously absorbed are also nowintensively being made. Agents for enhancing percutaneous permeabilityof aqueous drugs are now being studied, and especially, fatty acids andterpenes are mainly studied as candidates of the agents (J. Pharm.Pharmacol., 39, 535 (1987); J. Pharm. Sci., 80, 39 (1991); Drug Des.Delivery, 1, 245 (1987); Drug Des. Delivery, 6, 229 (1990); DrugDelivery System, 6, 5 (1991); Japanese Laid-open Patent Application(Kokai) Nos. 3-261721, 2-3613 and 60-36423; and Japanese Laid-open PCTApplication (Kohyo) Nos. 2-503672 and 63-502108).

On the other hand, preparations to be percutaneously absorbed, whichcomprise PGs such as PGI₂, are also now being intensively studied(Japanese Laid-open Patent Application (Kokai) Nos. 58-124778, 4-22808,4-138187, 4-243827, 4-164034, 63-211241 and 4-312520; and JapaneseLaid-open PCT Application (Kohyo) No. 6-509346).

However, these preparations for subcutaneous absorption containing PGI₂derivatives do not necessarily have satisfactory percutaneouspermeability.

DISCLOSURE OF THE INVENTION

The present invention provides a preparation to be percutaneouslyabsorbed comprising a PGI₂ derivative as an effective ingredient and afatty acid, a derivative thereof, or a mixture of two or more of these,which has a high percutaneous permeability of the PGI₂ derivative,especially a preparation to be percutaneously absorbed comprising5,6,7-trinor-4,8-inter-m-phenylene derivative and a C₆ -C₂₄ fatty acidor a salt or an ester thereof, or a mixture of two or more of these,which has a high percutaneous permeability of the PGI₂ derivative.

BEST MODE FOR CARRYING OUT THE INVENTION

To overcome the above-described problems, the present inventorsintensively studied to discover that a preparation for subcutaneousabsorption, which gives high percutaneous permeability of the PGI₂derivative, is obtained by selecting a base component and an agent forenhancing percutaneous permeability, thereby completing the presentinvention.

That is, the present invention provides a preparation for percutaneousabsorption comprising as an effective component a PGI₂ derivative and afatty acid or a derivative thereof.

As the PGI₂ derivative which may be employed in the present invention,one having excellent stability and having plateletaggregation-inhibition activity and vasodilation activity is selected.For example, the compound of the formula (I): ##STR1## (wherein R₁represents a pharmaceutically acceptable cation, hydrogen or C₁ -C₁₂linear alkyl group; R₂ represents hydrogen, C₂ -C₁₀ acyl group or C₇-C₁₈ aroyl group; R₃ represents hydrogen, C₂ -C₁₀ acyl group or C₇ -C₁₈aroyl group; R₄ represents hydrogen, methyl group or ethyl group; nrepresents 0 or an integer of 1 to 4; R₅ represents C₁ -C₅ linear alkylgroup; A represents i) --CH₂ --CH₂ -- or ii) trans--CH═CH--; and Xrepresents i) --CH₂ --CH₂ -- or ii) trans--CH═CH--) and salts and estersthereof may be employed in the present invention.

Preferred examples of the PGI₂ derivative include(±)-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-(E)-(3S*)-3-hydroxy-4-methyl-1-octene-6-ynyl)-1H-cyclopentab!benzofuran-5-butyric acid (hereinafter referred to as "beraprost"),and salts and esters thereof.

The concentration of the effective ingredient in the preparation is notlimited as long as it gives therapeutic effect, and may be, for example,0.00005 to 0.1%, preferably 0.0001 to 0.05%.

Examples of the fatty acids, salts thereof and esters thereof, which maybe employed as the agent for enhancing percutaneous permeability,include C₆ -C₂₄ fatty acid, salts thereof and esters thereof, such ascaproic acid, caprylic acid, capric acid, lauric acid, myristic acid,palmitic acid, isopalmitic acid, stearic acid, isostearic acid, arachicacid, behenic acid, lignoceric acid, myristoleic acid, palmitoleic acid,oleic acid, linoleic acid, linolenic acid, arachidonic acid, erucicacid, docosahexaenic acid and tetracosenic acid, as well as salts andesters thereof, and mixtures of two or more of these. Among these,preferred examples include C₈ -C₁₈ saturated fatty acids such ascaprylic acid, capric acid, lauric acid, myristic acid, palmitic acidand stearic acid; C₁₆ -C₂₂ unsaturated fatty acids such as palmitoleicacid, oleic acid, linoleic acid, linolenic acid, arachidonic acid,erucic acid and docosahexaenic acid; salts and esters of these, andmixtures of two or more of these. Especially preferred examples includeC₁₀ -C₁₄ saturated fatty acids such as capric acid, lauric acid andmyristic acid; C₁₈ unsaturated fatty acids such as oleic acid andlinoleic acid; salts and esters of these, and mixtures of two or more ofthese. The content of the percutaneous permeability-enhancing agent maybe, for example, 0.01 to 10% based on the total preparation. The contentmay preferably be 1 to 5%, more preferably 1 to 3%.

As the base, any base which is used in preparations for percutaneousabsorption may be employed. Examples of the base which may be employedin the present invention include silicone oils, white vaseline,plastibase, liquid paraffin, alcohol-based bases, glycol-based bases,pressure-sensitive silicone adhesives, silicone rubbers,styrene-isobutyrene-styrene block copolymer rubbers, polyisoprenerubbers, polyisobutyrene rubbers, styrene-butadiene rubbers, butylrubbers, natural rubbers, polyvinylalkyl ethers, poly(meth)acrylates,polyurethanes, polyamides, ethylene-vinyl acetate copolymers, alkylacrylate-acrylic acid copolymers and hydroxypropylcellulose as well asmixtures of two or more of these. Among these, silicone oils,pressure-sensitive silicone adhesives, silicone rubbers, naturalrubbers, poly(meth)acrylic acid-based adhesives and mixtures of two ormore of these are preferred.

The preparation according to the present invention may comprise usableadditives such as antiseptics, agents for giving adhesiveness,solubilizers, absorption co-enhancers, stabilizers and the like asrequired.

The preparation according to the present invention may be formulatedinto a formulation which can be percutaneously administered, such asointment, liquid for external use or tape, by a conventional process.

The preparation according to the present invention is a stable andlasting preparation. By applying or attaching the preparation on the armor chest and exchanging the preparation once or several times a day oronce or several times a week, stable pharmacological effects can beobtained with high safety, so that administration of the preparation iseasy.

The preparation according to the present invention aims at a topical orsystemic action, and may be used as an antiulcer agent against gastriculcer or duodenal ulcer; therapeutic agent for trauma against bedsore,burn ulcer, angiopathic ulcer, diabetic ulcer, ulcer accompanied byperipheral circulatory disturbance or hemorrhoid; antithrombotic drugagainst cerebral infarction, peripheral circulatory disturbance,myocardial infarction or angina pectoris; antihypertensive agent;therapeutic agent for diabetic neuropathy; drug for arteriosclerosis;drug for hyperlipidemia; therapeutic agent for hepatic diseases; or asan agent for inhibiting metastasis of malignant tumors.

EXAMPLES

The present invention will now be described in more detail referring toformulation examples. However, the present invention is not restrictedby these examples.

    ______________________________________                                                             Liquid                                                   ______________________________________                                        Formulation Example 1                                                         beraprost sodium salt  0.5    g                                               caproic acid           2.5    g                                               silicone oil           500    g                                               Formulation Example 2                                                         beraprost sodium salt  0.5    g                                               caprylic acid          2.5    g                                               silicone oil           500    g                                               Formulation Example 3                                                         beraprost sodium salt  0.5    g                                               capric acid            2.5    g                                               silicone oil           500    g                                               Formulation Example 4                                                         beraprost sodium salt  0.5    g                                               lauric acid            2.5    g                                               silicone oil           500    g                                               Formulation Example 5                                                         beraprost sodium salt  0.5    g                                               myristic acid          2.5    g                                               silicone oil           500    g                                               Formulation Example 6                                                         beraprost sodium salt  0.5    g                                               palmitic acid          2.5    g                                               silicone oil           500    g                                               Formulation Example 7                                                         beraprost sodium salt  0.5    g                                               stearic acid           2.5    g                                               silicone oil           500    g                                               Formulation Example 8                                                         beraprost sodium salt  0.5    g                                               arachidonic acid       2.5    g                                               silicone oil           500    g                                               Formulation Example 9                                                         beraprost sodium salt  0.5    g                                               oleic acid             2.5    g                                               silicone oil           500    g                                               Formulation Example 10                                                        beraprost sodium salt  0.5    g                                               linoleic acid          2.5    g                                               silicone oil           500    g                                               Formulation Example 11                                                        beraprost sodium salt  0.5    g                                               linolenic acid         2.5    g                                               silicone oil           500    g                                               Formulation Example 12                                                        beraprost sodium salt  0.5    g                                               oleic acid             1.5    g                                               silicone oil           500    g                                               Formulation Example 13                                                        beraprost sodium salt  0.5    g                                               capric acid            1.5    g                                               silicone oil           500    g                                               ______________________________________                                    

The above-described liquids were prepared by dissolving 0.5 g ofberaprost sodium salt in 1.5 g or 2.5 g of each fatty acid and uniformlymixing the resulting solution with 500 g of silicone oil.

    ______________________________________                                                             Ointment                                                 ______________________________________                                        Formulation Example 14                                                        beraprost sodium salt  0.5    g                                               capric acid            2.5    g                                               white vaseline         450    g                                               liquid paraffin        50     g                                               Formulation Example 15                                                        beraprost sodium salt  0.5    g                                               oleic acid             2.5    g                                               white vaseline         450    g                                               Liquid paraffin        50     g                                               Formulation Example 16                                                        beraprost sodium salt  0.5    g                                               linolenic acid         2.5    g                                               white vaseline         45.0   g                                               liquid paraffin        50     g                                               ______________________________________                                    

The above-described ointments were prepared by mixing a solutioncontaining 0.5 g of beraprost sodium salt in 2.5 g of capric acid with50 g of liquid paraffin and by mixing the resultant with 450 g of warmedwhite vaseline, followed by cooling the obtained mixture.

    ______________________________________                                                               Tape                                                   ______________________________________                                        Formulation Example 17                                                        beraprost sodium salt    0.5   g                                              capric acid              2.5   g                                              pressure-sensitive silicone adhesive                                                                   250   g                                              heptane                  250   g                                              Formulation Example 18                                                        beraprost sodium salt    0.5   g                                              oleic acid               2.5   g                                              pressure-sensitive silicone adhesive                                                                   250   g                                              heptane                  250   g                                              Formulation Example 19                                                        beraprost sodium salt    0.5   g                                              oleic acid               21.5  g                                              poly(meth)acrylic acid-based adhesives                                                                 250   g                                              Formulation Example 20                                                        beraprost sodium salt    0.5   g                                              oleic acid               2.5   g                                              styrene-isobutyrene base 250   g                                              ______________________________________                                    

The above-described tapes were prepared as follows. First, 0.5 g ofberaprost sodium salt is dissolved in 2.5 g of oleic acid and theresulting solution is mixed with an appropriate amount of a solvent. Theresultant is mixed with 250 g of the adhesive base and the viscosity ofthe mixture is adjusted by adding a solvent. The resulting mixture iscast on a PET film and the obtained film is dried in the air.

    ______________________________________                                        Formulation Example 21                                                                            Liquid                                                    ______________________________________                                        beraprost sodium salt                                                                             0.5      g                                                silicone oil        500      g                                                ethanol             appropriate amount                                        ______________________________________                                    

This liquid was prepared by dissolving 0.5 g of beraprost sodium salt ina small amount of ethanol, and uniformly mixing the resulting solutionwith 500 g of silicone oil, followed by evaporation of the ethanol underreduced pressure.

    ______________________________________                                        Formulation Example 22                                                                            Ointment                                                  ______________________________________                                        beraprost sodium salt                                                                             0.5      g                                                white vaseline      450      g                                                liquid paraffin     50       g                                                ethanol             appropriate amount                                        ______________________________________                                    

This ointment was prepared by dissolving 0.5 g of beraprost sodium saltin a small amount of ethanol, and mixing the resulting solution with 50g of liquid paraffin, followed by uniformly mixing the resultingsolution with 450 g of warmed white vaseline and cooling the obtainedcomposition.

    ______________________________________                                        Formulation Example 23                                                                            Tape                                                      ______________________________________                                        beraprost sodium salt                                                                             0.5      g                                                pressure-sensitive silicone adhesive                                                              256      g                                                heptane             250      g                                                ethanol             appropriate amount                                        ______________________________________                                    

This tape was prepared as follows. First, 0.5 g of beraprost sodium saltis dissolved in a small amount of ethanol, and the resultant is mixedwith 250 g of heptane, followed by mixing the resulting solution with250 g of the pressure-sensitive silicone adhesive. The resulting mixtureis cast on a PET film and the obtained film is dried in the air.

Example 1 In vitro Percutaneous Permeation Test of Beraprost Sodium SaltUsing Skin of Back of Hairless Mouse

To confirm the effect of the preparations for enhancing percutaneousabsorption of beraprost sodium salt, a percutaneous permeation test wascarried out.

The skin excised from the back of a hairless mouse was mounted in aLoveday type diffusion cell, and each of the preparations according toFormulation Examples 1 to 11 and according to Comparative Example 1 wasapplied on the upper portion of the skin. Physiological saline was usedas the receptor phase and the percutaneous permeation test was carriedout at 25° C. The results are shown in Table 1.

As can be seen from the test results, the preparations according toFormulation Examples 1 to 11 exhibited higher percutaneous permeabilitythan the preparation according to Comparative Example 1 in which noagent for enhancing percutaneous absorption was contained. Further, itwas found that the effect for enhancing percutaneous permeabilitydiffers depending on the type of the fatty acid.

                  TABLE 1                                                         ______________________________________                                        Rate of Percutaneous Perrneation in vitro of                                  Beraprost through Skin of Back of Hairless Mouse                                              Rate of Percutaneous                                          Formulation Example                                                                           Permeability (μg/hr/cm.sup.2)                              ______________________________________                                        Comparative Example 1                                                                         0.00                                                          Formulation Example 1                                                                         0.89                                                          Formulation Example 2                                                                         1.06                                                          Formulation Example 3                                                                         2.09                                                          Formulation Example 4                                                                         2.51                                                          Formulation Example 5                                                                         2.03                                                          Formulation Example 6                                                                         0.25                                                          Formulation Example 7                                                                         0.53                                                          Formuiation Example 8                                                                         0.14                                                          Formulation Example 9                                                                         2.39                                                          Formulation Example 10                                                                        3.01                                                          Formulation Example 11                                                                        1.41                                                          ______________________________________                                    

Example 2 Percutaneous Absorption Test In Vivo of Beraprost Sodium SaltUsing Rats

To evaluate the transportation of beraprost sodium salt from skin to theblood circulatory system in vivo, a percutaneous absorption test wascarried out using rats to confirm the effectiveness of the percutaneousabsorption enhancers.

Hair was removed from the skin of back of each rat, and the tape havinga size of 1 cm×1 cm formulated in accordance with Formulation Examples17 to 19 or in accordance with Comparative Example 3 was patched. Afterpatching the tape, blood was collected from the caudal vein at timepoints and blood drug level was measured.

As can be seen from the test results shown in Table 2, substantially nodrug was detected in Comparative Example 3, while in cases while thetape according to Formulation Examples 17 to 19 was patched, the blooddrug level was prominently high, and it was confirmed that absorption ofthe drug lasted.

                  TABLE 2                                                         ______________________________________                                        Blood Drug Level in Rats after Patching                                       Silicone Tape Containing Beraprost Sodium Salt                                Time Point                                                                              Blood Drug Level (pg/ml) *1                                         of Blood  Comparative                                                                             Example   Example                                                                              Example                                  Collection                                                                              Example 3 15        16     17                                       ______________________________________                                         0 hr     0 ± 0  0 ± 0  0 ± 0                                                                             0 ± 0                                  6 hr     0 ± 0  301 ± 246                                                                            387 ± 224                                                                         91 ± 90                               12 hr     14 ± 14                                                                              692 ± 591                                                                            802 ± 500                                                                         105 ± 125                             24 hr     0 ± 0  278 ± 223                                                                            809 ± 232                                                                         200 ± 132                             48 hr     19 ± 42                                                                              387 ± 297                                                                            710 ± 221                                                                         161 ± 110                             ______________________________________                                         *1: mean ± standard error (n = 5)                                     

Example 3 Therapeutic Effect of Beraprost Sodium Salt Against Occlusionof Peripheral Artery in Rabbit Models Induced by Sodium Laurate

To confirm the pharmacological effectiveness in vivo of the preparationsaccording to the present invention, the effectiveness of the absorptionenhancers was evaluated using rabbit models of occlusion of peripheralartery induced by lauric acid.

Hair on both ears of each male Japanese White rabbit (2.5-3.0 kg) wasremoved with an animal clipper. Into the auricular artery behind theright ear of each rabbit, 5 mg of sodium laurate (in 10 mM isotonicphosphate buffer, pH 7.4) was injected to induce occlusion of peripheralartery.

The preparations according to Formulation Examples 12 and 13 andaccording to Comparative Example 1 were tested. In each adhesive bandage(2.25 cm²) for patch test, 0.1 ml of the test preparation wasimpregnated, and the adhesive bandage was patched on the left ear once aday. The progress of the lesion in the right ear was observed with timeand scored according to the following criteria:

Score of Lesion in Right Ear

0; normal, 1; color is changed in the tip of the ear, 2; color ischanged in the entire ear, 3; necrosis occurred in the tip of the ear,4; necrosis occurred in the entire ear, 5; deciduation of necrosedportion began.

As can be seen from the test results shown in Table 3, in the group towhich silicone oil base was administered, severe occlusion of bloodvessels occurred by administration of sodium laurate, and on the 7th dayafter the administration, color change or tissue necrosis was observedin large area in the tip of the right ear. In the group to which thepreparation according to Comparative Example 1 was administered, whichdoes not contain an absorption enhancer, the progress of the lesion wasslightly prevented by the everyday administration when compared with thegroup to which only the base was administered.

On the other hand, in the group to which the preparations according toFormulation Example 12 or 13 containing oleic acid or capric acid as anabsorption enhancer was administered, prominent inhibition of progressof the lesion was observed, due to the percutaneous absorption-enhancingeffect confirmed in Examples 1 and 2. Especially, in the group to whichthe preparation according to Formulation Example 12 was administered,healing began to be observed at 3 days after the patching, and healed tosubstantially normal state at 7 days after patching.

                  TABLE 3                                                         ______________________________________                                        Therapeutic Effect of Beraprost Sodium Salt                                   Against Occlusion of Peripheral Artery in Rabbit Models                       Induced by Sodium Laurate                                                     Healing Score of Lesion in the Right Ear                                      Group                                                                         Time  Administered                                                                             Comparative                                                                              Formulation                                                                           Formulation                               (day) with Base  Example 1  Example 12                                                                            Example 13                                ______________________________________                                        0     0.0 ± 0.0                                                                             0.0 ± 0.0                                                                             0.0 ± 0.0                                                                          0.0 ± 0.0                              1     1.2 ± 0.2                                                                             1.0 ± 0.0                                                                             0.8 ± 0.0                                                                          0.8 ± 0.3                              2     1.6 ± 0.2                                                                             1.3 ± 0.2                                                                             0.7 ± 0.0*                                                                         0.8 ± 0.2*                             3     2.3 ± 0.0                                                                             1.8 ± 0.2                                                                             0.7 ± 0.2*                                                                         1.0 ± 0.3*                             4     3.0 ± 0.3                                                                             2.5 ± 1.0                                                                             0.5 ± 0.0*                                                                         1.2 ± 0.4*                             5     3.5 ± 0.3                                                                             2.5 ± 1.5                                                                             0.4 ± 0.1*                                                                         1.0 ± 0.5*                             6     4.2 ± 0.1                                                                             2.5 ± 1.5                                                                             0.2 ± 0.2*                                                                         0.8 ± 0.5*                             7     4.5 ± 0.3                                                                             2.5 ± 1.5                                                                             0.2 ± 0.2*                                                                         0.6 ± 0.4*                             ______________________________________                                         Mean of scores of healing effect ± standard deviation (N = 3).             Significant difference with respect to the group to which preparation         according to Comparative Example 1 was administered:                          *p < 0.05.                                                               

By the present invention, it was confirmed that PGI₂ derivatives can bequickly absorbed from the skin into the body by addition of apercutaneous permeation enhancer and a high blood level can be kept fora long time. Thus, by the present invention, a preparation forpercutaneous absorption having high percutaneous permeability of PGI₂derivatives was provided.

This suggests a possibility to last pharmacological effects and toreduce side effects. Thus, the preparation is expected to be used fortherapy of various diseases, aiming at topical and systemic actions.

We claim:
 1. A preparation for percutaneous absorption comprising as an effective component, a prostaglandin I₂ derivative; and a C₈ -C₁₄ saturated or C₁₆ -C₂₂ unsaturated fatty acid, a derivative thereof, a salt thereof, or mixtures thereof.
 2. The preparation according to claim 1, wherein said effective component is a compound of the formula (I): ##STR2## wherein R₁ represents a pharmaceutically acceptable cation, hydrogen or C₁ -C₁₂ linear alkyl group;R₂ represents hydrogen, C₂ -C₁₀ acyl group or C₇ -C₁₈ aroyl group; R₃ represents hydrogen, C₂ -C₁₀ acyl group or C₇ -C₁₈ aroyl group; R₄ represents hydrogen, methyl group or ethyl group; n represents 0 or an integer of 1 to 4; R₅ represents C₁ -C₅ linear alkyl group; A represents --CH₂ --CH₂ -- or trans--CH═CH--; and X represents --CH₂ --CH₂ -- or trans--CH═CH-- or a salt or an ester thereof.
 3. The preparation according to claim 1, wherein said prostaglandin I₂ derivative is (±)-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2-hydroxy-1- (E)-(3S*)-3-hydroxy-4-methyl-1-octene-6-ynyl)-1H-cyclopenta b!benzofuran-5-butyric acid; or a salt or an ester thereof.
 4. The preparation according to claim 1, wherein said saturated fatty acid is caprylic acid, capric acid, lauric acid, myristic acid, and said unsaturated fatty acid is palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, erucic acid or docosahexaenic acid.
 5. The preparation according to claim 1, wherein said fatty acid or a derivative thereof is a C₁₀ -C₁₄ saturated fatty acid, C₁₈ unsaturated fatty acid, a salt thereof, or a mixture of two or more of these.
 6. The preparation according to claim 5, wherein said saturated fatty acid is capric acid, lauric acid or myristic acid, and said unsaturated fatty acid is oleic acid or linoleic acid.
 7. The preparation according to claim 1, wherein said fatty acid is a C₁₀ -C₁₄ saturated fatty acid.
 8. The preparation according to claim 1, wherein said fatty acid is a C₁₈ unsaturated fatty acid. 